This application relates to a process for producing bis-silyl derivatives of fluorinated pyrimidines, and to a process for producing nucleosides of pyrimidines, utilizing the bis-silyl derivative as an intermediate product.
U.S. Pat. No. 3,354,160 to Duschinsky et al, issued Nov. 21, 1967, discloses a process for preparing nucleosides of 5-fluorouracil and 5-fluorocytosine by reacting 5-fluorouracil or 5-fluorocytosine with hexa(lower alkyl)disilazane to form the corresponding bis-tri(lower alkyl) silyl-5-fluoropyrimidine intermediate compound, which can be subsequently condensed with an appropriate blocked sugar halide, and unblocked to form the desired nucleoside derivative.
Among the hexa(lower alkyl)disilazanes disclosed as suitable for the reaction of the aforesaid U.S. Pat. No. 3,354,160 is hexamethyldisilazane, sometimes known as HMDS.
The alkylation reaction of the aforesaid U.S. patent proceeds in high yields. However, one source of low process efficiency in the preparation of the desired nucleosides is in the preparation of the starting 5-fluorouracil or 5-fluorocytosine compound. Various methods of making these compounds are known to the prior art. Particularly preferred methods of making these compounds are disclosed in U.S. Pat. applications Nos. 186,444 and 271,489 filed Oct. 4, 1971 now U.S. Pat. No. 3,954,758 and July 13, 1972, respectively, the disclosures of which are hereby incorporated by reference. As disclosed in those applications, intermediate 5,6-dihydro compounds are formed which carry a 6-position hydroxy or alkoxy radical. These 5,6-dihydro compounds undergo an elimination reaction to obtain the desired 5-fluorouracil compound. Such a reaction involves a product loss of about 15%, on the conversion of uracil fluorohydrin to 5-fluorouracil.
U.S. Pat. No. 3,635,946, to Giller et al., issued Jan. 18, 1972 is directed to a process for preparing nucleosides of 5-substituted uracils by reacting 2-chlorofuranidine with bis-trimethylsilyl derivatives of the corresponding uracil. The reaction is conducted at a temperature of from -60 to +40.degree. C, and the working examples (Examples 8 and 9) indicate that 50% and 65% yields, based on the theoretical yield, are obtained.